The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model.

Background: Nearly half of all individuals with Down Syndrome (DS) have some type of congenital heart defect (CHD), suggesting that DS sensitizes to CHD but does not cause it. We used a common mouse model of DS, the Ts65Dn mouse, to study the contribution of Tbx5, a known modifier of CHD, to heart defects on a trisomic backgroun. Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice.

A Sonic hedgehog (Shh) response deficit in trisomic cells may be a common denominator for multiple features of Down syndrome.

The hedgehog (HH) family of growth factors is involved in many aspects of growth and development, from the establishment of left-right axes at gastrulation to the patterning and formation of multiple structures in essentially every tissue, to the maintenance and regulation of stem cell populations in adults. Sonic hedgehog (Shh) in particular acts as a mitogen, regulating proliferation of target cells, a growth factor that triggers differentiation in target populations, and a morphogen causing cells to respond differently based on their positions along a spatial and temporal concentration gradient. Given its very broad range of effects in development, it is not surprising that many of the structures affected by a disruption in Shh signaling are also affected in Down syndrome (DS).